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Immunoprofiling and survival in PTL
tumors has indeed gained a lot of attention recently. Antibodies targeting inhibitory molecules, such as PD-1, PD-L1, and CTLA-4 that regulate T-cell cytotoxicity have achieved impressive clinical responses.27-29 However, despite clear clinical responses, only a fraction of patients respond to treatment. Based on the findings from solid tumors, it has been suggested that the status of the HLA machinery affects the success of immunotherapy. For example, inactivating mutations in the β2M and HLA I complex in lung cancer caused a lack of response to immunotherapy because the cytotoxic cells were unable to find and attack the tumor cells.30 It was suggested that the recurrent inactivation of HLA I is an acquired mecha- nism for avoiding tumor immune recognition. In lym- phomas, novel immunotherapies, including bispecific antibodies, cancer vaccines, and chimeric antigen receptor (CAR)-T cells may help T cells to identify and attack can- cer cells.31-36 Another therapeutic implication that could be tested is to recuperate the loss of HLA II expression and the subsequent inability of T cells to recognize lymphoma cells by using histone deacetylase inhibitors.37,38
In conclusion, we have combined immune gene signa- tures and mIHC data with clinical information in a cohort of patients with PTL. We found three immune signatures, of which the T-lymphocyte signature was associated with survival both in PTL and DLBCL. The patients with T-cell-
inflamed TME had a significantly increased risk of pro- gression and death independently of IPI. Furthermore, reduced membranous staining of HLA I and II correlated with low T-cell infiltration. Taken together, the results presented herein are novel and emphasize the importance of immune escape as a mechanism regulating therapy resistance in patients with PTL.
Acknowledgments
We thank Dr. Petri Auvinen and Lars Paulin (Institute of Biotechnology, University of Helsinki, Finland) for the Nanostring analyses. Anne Aarnio and Marika Tuukkanen are acknowledged for technical assistance. The DLBCL dataset is part of the Cancer Genomics Characterization Initiative (CGCI), supported by NCI contract N01-C0-12400 (http://cgap.nci.nih.gov/cgci.html).
Funding
This work was supported by grants from the Academy of Finland (to SL); Finnish Cancer Foundation (to SL and SMu); Finnish Cancer Institute (to SMu); Sigrid Juselius Foundation (to SL and SMu); Gyllenberg Foundation (to SMu); University of Helsinki (to SL); Helsinki University Hospital (to SL and SMu); Pirkanmaa Cancer Society (to MP); Seppo Nieminen Foundation (to MP); Eino Saarinen Foundation (to MP); and Finnish Oncology Association (to MP).
References
1. Cheah CY, Wirth A, Seymour JF. Primary testicular lymphoma. Blood. 2014; 123(4):486-493.
2. Deng L, Xu-Monette ZY, Loghavi S, et al. Primary testicular diffuse large B-cell lym- phoma displays distinct clinical and biolog- ical features for treatment failure in ritux- imab era: a report from the International PTL Consortium. Leukemia. 2016; 30(2):361-372.
3. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14(8):517-534.
4. Shain KH, Dalton WS, Tao J. The tumor microenvironment shapes hallmarks of mature B-cell malignancies. Oncogene. 2015;34(36):4673-4682.
5. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013; 14(10):1014-1022.
6. Nicholas NS, Apollonio B, Ramsay AG. Tumor microenvironment (TME)-driven immune suppression in B cell malignancy. Biochim Biophys Acta. 2016;1863(3):471- 482.
7. Booman M, Douwes J, Glas AM, et al. Mechanisms and effects of loss of human leukocyte antigen class II expression in immune-privileged site-associated B-cell lymphoma. Clin Cancer Res. 2006; 12(9):2698-2705.
8. Challa-Malladi M, Lieu YK, Califano O, et al. Combined genetic inactivation of beta2- Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell. 2011;20(6):728-740.
9. Nijland M, Veenstra RN, Visser L, et al. HLA dependent immune escape mecha-
nisms in B-cell lymphomas: Implications for immune checkpoint inhibitor therapy? Oncoimmunology. 2017;6(4):e1295202.
10. Riemersma SA, Jordanova ES, Schop RF, et al. Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites. Blood. 2000;96(10):3569-3577.
11. Riemersma SA, Oudejans JJ, Vonk MJ, et al. High numbers of tumour-infiltrating acti- vated cytotoxic T lymphocytes, and fre- quent loss of HLA class I and II expression, are features of aggressive B cell lymphomas of the brain and testis. J Pathol. 2005;206(3):328-336.
12. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classifica- tion of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282.
13. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476(7360):298-303.
14. Blom S, Paavolainen L, Bychkov D, et al. Systems pathology by multiplexed immunohistochemistry and whole-slide digital image analysis. Sci Rep. 2017;7(1):15580.
15. Carpenter AE, Jones TR, Lamprecht MR, et al. CellProfiler: image analysis software for identifying and quantifying cell pheno- types. Genome Biol. 2006;7(10):R100.
16. Ansell SM, Stenson M, Habermann TM, Jelinek DF, Witzig TE. Cd4+ T-cell immune response to large B-cell non-Hodgkin's lymphoma predicts patient outcome. J Clin Oncol. 2001;19(3):720-726.
17. Keane C, Gill D, Vari F, Cross D, Griffiths L, Gandhi M. CD4(+) tumor infiltrating lym- phocytes are prognostic and independent
of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy. Am J Hematol. 2013;88(4):273-276.
18. Keane C, Vari F, Hertzberg M, et al. Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in dif- fuse large B-cell lymphoma: a population- based study. Lancet Haematol. 2015;2(10):e445-455.
19. Rimsza LM, Roberts RA, Miller TP, et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosur- veillance and poor patient survival regard- less of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood. 2004;103(11):4251-4258.
20. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28(6):690-714.
21. Abes R, Gelize E, Fridman WH, Teillaud JL. Long-lasting antitumor protection by anti- CD20 antibody through cellular immune response. Blood. 2010;116(6):926-934.
22. Battella S, Cox MC, La Scaleia R, et al. Peripheral blood T cell alterations in newly diagnosed diffuse large B cell lymphoma patients and their long-term dynamics upon rituximab-based chemoimmunother- apy. Cancer Immunol Immunother. 2017;66(10):1295-1306.
23. Hilchey SP, Hyrien O, Mosmann TR, et al. Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a "vaccinal effect" of rituximab. Blood. 2009;113(16):3809- 3812.
24. Spranger S, Bao R, Gajewski TF.
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